Drug Approval Processes May Have Delayed Safety Warnings for Antidepressants

Following GlaxoSmithKline's recent letter to doctors pointing to a sixfold increase in the risk of suicidal behaviour in adults taking paroxetine, Professor David Healy examines the regulation of selective serotonin reuptake inhibitors (SSRIs) and asks were mistakes made and could they have been avoided?

In February 1990 an article raised concerns that the recently licensed fluoxetine might trigger suicide acts in depressed patients. Subsequent trials showed a doubling of rates of suicidal acts between active treatment and placebo, but it was only in a recent study reviewing over 700 trials that this difference became significant.

This trend should have been seen by both companies and regulators as something that required investigation, writes the author.

Trials in children conducted from the mid-1990s also show a doubling of the risks of suicidal acts with SSRIs. These results have recently formed the basis of warnings about the use of SSRIs in children. Trials in adults show a similar risk ratio yet, until May 2006, no warnings were issued for adults.

"Although data submitted to the FDA show an excess of suicides with every antidepressant licensed since 1987 compared with placebo, this simple but crucial finding continues to be obscured," he says.

He also examines the way in which the data were presented to regulators by manufacturers, and suggests that inappropriate inclusion of suicidal acts in the placebo group biased estimates of suicide risk. Subsequent "rigid interpretation" of these data by the regulators "may have delayed warnings of dangers of suicidal acts," he adds.

Having re-analysed the evidence, he suggests that the best estimate for the likely risk of suicide on SSRIs over placebo is 2.6 (more than double the risk) and he calls for suitably powered studies to settle the issue.

He also believes that greater data transparency and statistical sophistication might lead to earlier research to discriminate between those who do well on new drugs and those who do not.

"The regulators seem stuck in a world where balancing evidence of potential benefit against actual risk causes real problems," he writes. "The SSRI and rofecoxib disasters have harmed public confidence in drugs. We urgently need to learn how to regulate both the risks and benefits of new treatments more effectively."

BMJ Editor, Fiona Godlee also touches on this issue in her Editor's choice column. She talks of "an overpowerful under-regulated drug industry and a research establishment and publishing industry in its thrall." A radical solution would be to stop allowing drug companies to evaluate their own products. Is this feasible? Is it the answer? she asks.

British Medical Journal